Antibiotic introduction in the early 20th century ushered in a new era in the treatment of microbial infections, providing the medical community with powerful drugs in its battle against disease. In addition to being among the first drugs introduced, antibiotics are also among the most successful, saving countless lives, extending life spans, and permitting previously deadly medical procedures. They represent 5% of the global drug market, and provide $42 billion in annual sales (2009).1 One would be hard pressed to identify another drug class that enjoys such safe and widespread use, provides so successful health outcomes at such a modest cost, and has such a large economic impact. However, and from the very outset, this new revolution came with the concomitant induction of bacterial resistance to these treatments. The first reports of resistance followed only one year after the initial introduction of penicillin. Similarly, the introduction of methicillin in 1959, the next-generation drug for the treatment of penicillin-resistant strains, was followed only two years later by the emergence of methicillin-resistant Staphylococcus aureus (MRSA).2 This cycle continues to be repeated again and again as new antibiotics are discovered and introduced into widespread use.
The glycopeptide antibiotics have long stood as an exception to this phenomenon. The lack of significant levels of clinical resistance to the two most commonly deployed members, vancomycin and teicoplanin, led to their adoption as drugs of last resort for the treatment of otherwise resistant and deadly infections. Recent years however have finally brought the onset of resistance to these important drugs. Herein, we review the origin of the past success with the glycopeptides antibiotics and the science behind the development of derivatives that address the emerging problem of acquired resistance in pathogenic bacteria, which we believe will provide an even more powerful future class of antibiotics than Nature could devise.
Vancomycin is the leading member of the class of clinically important glycopeptide antibiotics. Discovered at Eli Lilly, vancomycin was first disclosed in 19563 and introduced into the clinic in 1958, although its structure was not established until nearly 30 years later in 1983.4 Following the emergence of MRSA, it became the drug of choice to treat resistant bacterial infections and it is also used for the treatment of patients on dialysis, undergoing cancer chemotherapy, or allergic to β-lactam antibiotics.5 Today, more than 60% of the ICU S. aureus infections are MRSA, and its movement from a hospital-acquired to a community-acquired infection has intensified the impact of such resistant bacterial infections.6 The onset of vancomycin resistance was long-delayed in comparison to all other antibiotics. Even after its first three decades of use, there was no notable resistance to vancomycin reported, and some even speculated that the development of resistance might be impossible.7 Vancomycin resistant phenotypes were first reported in enterococci (VRE) in 1987, many years after the introduction of the drug into widespread clinical use, and today >30% of the ICU Enterococcus faecalis infections are VRE. Following the emergence of resistance in enterococci, which is now genetically transferred vertically, concern arose over the emergence of vancomycin-resistant S. aureus (VRSA) as a result of horizontal gene transfer from resistant enterococci. The first cases of fully vancomycin-resistant strains were reported in 2002,8 and there have been an increasing number of cases of VRSA in the United States confirmed by the CDC.9 A majority of VRSA has been found in patients co-infected with VRE, implicating horizontal gene transfer as the current method for acquiring vancomycin resistance.10 As the prevalence of VRSA increases and as it establishes vertical gene transfer of resistance, new antibiotics with the longevity and dependability of vancomycin will be required to contain their impact. This need is arising at the same time that antibiotic discovery efforts are being discontinued at most major pharmaceutical companies. The reasons for this decline in antibiotic development are largely economic, resulting from a combination of patient short term use, the restricted use of new antibiotics with activity against resistant bacteria, and the increased regulatory criteria for approval.
Molecular Basis of Vancomycin Resistance
The mechanism of action of glycopeptide antibiotics involves the inhibition of bacterial cell wall synthesis by binding and sequestration of the integral precursor peptidoglycan peptide terminus D-alanine-D-alanine (D-Ala-D-Ala) in the developing cell wall, FIG. 1.11 This precursor is tightly bound by the antibiotic, physically preventing transpeptidation and transglycosylation, arresting cell wall cross-linking and maturation, and leading to cell lysis. In the two most prominent manifestations of resistance (VanA and VanB), this cell wall precursor is remodeled to D-alanine-D-lactate (D-Ala-D-Lac), incorporating an ester linkage in place of the amide of the natural ligand.12 Vancomycin-resistant bacteria sense the antibiotic challenge and subsequently remodel their precursor peptidoglycan terminus from D-Ala-D-Ala to D-Ala-D-Lac. Normal synthesis of lipid intermediate I and II, containing the D-Ala-D-Ala termini, continues but a late stage remodeling to D-Ala-D-Lac ensues to avoid the action of vancomycin. The binding affinity of the antibiotic for this altered ligand is reduced 1000-fold, resulting in a corresponding 1000-fold loss in antimicrobial activity.